Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
  • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
  • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
  • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
  • C07D501/36—Methylene radicals, substituted by sulfur atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• cephalosporium acremonium Since the isolation of an active antibiotic from the mold Cephalosporium acremonium and the identification of the chemical structure of its nucleus, 7-aminocephalosporanic acid, a profusion of cephalosporins has been synthesized. Like penicillins, the cephalosporins owe their antibacterial activity to the presence of the ⁇ -lactam ring. Some cephalosporins exhibit a broad range of antibacterial activity, including activity against organisms, notably staphylocacci, which are resistant to penicillins. Much of the broader range of activity shown by these cephalosporins over penicillins may be attributed to their resistance to a large number of ⁇ -lactamases which inactivate penicillins.
• Both penicillins and cephalosporins may be administered parenterally. However, some penicillins, notably, phenoxy penicillin, indanyl carbenicillin, inter alia, may also be administered orally. However, by comparison, only a few cephalosporins may be administered orally. Moreover, despite considerable efforts directed toward finding side chains that will impart oral absorbability in cephalosporins, e.g., by analogy to penicillins, only D-(-)-aryl- glycyl - or dihydrophenylglycyl- substituted cephalosporins possess significant oral absorption. Chemistry and Biology of B-Lactam Antibiotics, 1:391 (Robert B.
• the "prodrug” concept has been employed for both penicillins and cephalosporins; i.e., the administration of an inactive substance, such as an ester, which is metabolized by the body to an active component, e.g., the free acid.
• an inactive substance such as an ester
• an active component e.g., the free acid.
• esters For penicillins, several esters have been synthesized which will be metabolized to active antibiotics. Among such esters are pivaloyloxymethyl, methoxymethyl and indanyl.
• the prodrug concept has not been as successful with cephalosporins. Chemistry and Biology of ⁇ -Lactam Antibiotics, 1:404.
• cephalosporins in particular, whether an ester will render any given cephalosporin orally absorbable cannot be predicted.
• This invention relates to new cephalosporin esters which may be represented by the following formuals:
• R 1 is selected from the group consisting of hydrogen and C l -C 6 alkyl and R 2 is selected from the group consisting of C l -C 6 alkyl, aryl, (e.g., phenyl), adamantyl and -OR 3 , where R 3 is selected from the group consisting of C l -C 6 alkyl;
• R 4 is a cyclic system such as phthalidyl
• R 5 is selected from the group consisting of methoxy, decyloxy, and methylthio.
• Formula A compounds of the present invention may be prepared in accordance with the following Flowchart I.
• the cephalosporin compound (i), 76-[2-(2aminothiazol-4-yl)-(Z)-2-methoximinoacetamido]-3-[(1,2,3-thiadiazol-5-yl)-thiomethyl]ceph-3-em-4-carboxylic acid (described in Patent No. 4,399,132, which is incorporated herein by reference) is reacted with an appropriate alkylating agent (ii) in the presence of an acid acceptor, such as a tertiary amine, to produce the desired compound wherein R 1 and R 2 are as defined above.
• an acid acceptor such as a tertiary amine
• the sodium salt of (i) may be employed in the process shown in Flowchart I.
• Formula A compounds of the present invention may also be prepared in accordance with the following Flowchart III.
• cephalosporin compound (vi) is optionally protected with any suitable protecting group, e.g., t-butyloxycarbonyl, through use of di-t-butyl dicarbonate from Aldrich Chemical Co., Milwaukee, Wis., to form cephalosporin compound (vii), which is then reacted with an appropriate alkylating agent (ii) in the presence of an acid acceptor, such as a tertiary amine, to produce cephalosporin compound (viii).
• any suitable protecting group e.g., t-butyloxycarbonyl
• di-t-butyl dicarbonate from Aldrich Chemical Co., Milwaukee, Wis.
• cephalosporin compound (ix) which is then reacted with compound (x) in the presence of dicyclohexylcarbodiimide when R 6 is hydrogen and 1-hydroxybenzotriazole (or EEDQ when R 6 is trityl)co form cephalosporin of Formula A.
• Compound (ix) can also be synthesized directly from compound (vi) using the appropriate alkylating agent in the presence of an acid acceptor such as a tertiary amine.
• the amine group on compound (x) may optionally be protected, e.g., with trityl, chloroacetyl or formyl, when reacted with cephalosporins compound (ix), in which case such protecting group would be removed to yield compounds of Formula A.
• the amino group of cephalosporin (vi) may also be protected, if desired, with a trityl or 2-methoxycarbonyl-l-methylvinyl group.
• 76-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxim- inoacetamido]-3-[(1,2,3-thiadiazol-5-yl)-thiomethyl]-ceph-3- em-4-carboxylic acid is a potent, third generation cephalosporin that is administered parenterally.
• cephalosporin can be esterified to an orally-administratable pro-drug.
• prodrugs the compounds of the present invention exhibit significant oral in vivo activity in warm-blooded animals and the ratio of the subcutaneous/oral dose for most of the compounds is in the commercially acceptable range of about 4.0.
• the present invention in addition to providing a broad-spectrum oral cephalosporin that can be effectively utilized in the treatment of infections without hospitilization, the present invention also permits a patient to be treated for an infection both within and without the hospital with the same antibiotic. Oral formulations are also much preferred in pediatric use.
• the median effective doses (ED 50 ) in mg/kg were derived from the pooled data of three separate tests (including two range finding tests). The results of this testing appear in Table I.
• Other representative compounds of the present invention were similarly tested against a lethal infection of Klebsiella pneumoniae in mice. Charles River CD-1 mice, each weighing about 20g, were infected intraperitoneally with a lethal dose of Klebsiella pneumoniae.
• the median effective doses (ED 50 ) in mg/kg were derived from the pooled data of three separate tests (including two range finding tests).
• control 7 ⁇ -[2-(2-amino thiazol-4-yl (Z)-2-methoximinoacetamido]-3-[(1,2,3-thiadiazol-5-yl)-thiomethyl]ceph-3-em-4-carboxylic acid, provides a basis for comparison. All compounds were administered by single subcutaneous dose and single oral dose. The results of this test appear in Table II.
• the active compounds of the present invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsule shells, or they may be compressed into tablets, or they may be incorporated with.food.
• the active compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like.
• Such compostions and preparations should contain at least about 0.1% of active compound.
• the percentage of the active compounds of the present invention in therapeutic preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of a preparation.
• the amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
• the tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring.
• a binder such as gum tragacanth, acacia, corn starch or gelatin
• excipients such as dicalcium phosphate
• a disintegrating agent such as corn starch, alginic acid and the like
• a lubricant such as magnesium stearate
• a sweetening agent such as sucrose, lactose or saccharin
• a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring.
• tablets, pills or capsules may be coated with shellac, sugar or both.
• a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and pro- pylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
• any material used in preparing any dosage unit form should be pharmaceutically pure, substantially non-toxic in the amounts employed and non-reactive with the esters of the present invention.
• reaction mixture was stirred at room temperature for approximately 4.5 hours, then about 100 ml of water was added and the mixture was extracted with approximately two 50 ml portions of ethyl acetate. The ethyl acetate extracts were combined, washed with saturated aqueous sodium bicarbonate, then water and finally brine and dried over magnesium sulfate. Evaporation of the solvent gave a glass which was triturated with ether, giving a solid. Thin layer chromatography and nuclear magnetic resonance showed that the product was a mixture of the A 2 and ⁇ 3 isomers, IR 1775 cm -1 ( ⁇ -lactam carbonyl).
• Acetoxymethyl 75-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoximinoacetamido]-3-[(1,2,3-thiadiazol-5-yl)-thiomethyl]ceph-3-em-4-carboxylate (1.0g) was added to 10 ml of 80% aqueous formic acid and stirred at room temperature for 2 hours. Water (10 ml) was added and the mixture was filtered. The filtrate was evaporated to dryness at reduced pressure (bath temperature 40 0 ) and the residue was slurried in 25 ml of ethyl acetate and 25 ml of saturated sodium bicarbonate solution.
• the filtrate was diluted with 75 ml of ethyl acetate and extracted successively with 75 ml portions of water, saturated sodium bicarbonate solution, water and brine.
• the ethyl acetate layer was dried over magnesium sulfate and evaporated to dryness at reduced pressure. The residue was slurried in ethyl acetate and filtered. The filtrate was evaporated to dryness and the product was purified by chromatography on silica gel using ethyl acetate.
• Acetoxymethyl 7-[(t-butyloxycarbonyl)amino]-3-[(1,2,3-thiadiazol-5-yl)-thiomethyl]ceph-3-em-4-carboxylate (350 mg) was added to 4 ml of trifluoroacetic acid then evaporated at reduced pressure (40 0 ). The residue was slurried with 25 ml of ethyl acetate and 25 ml of saturated sodium bicarbonate solution. The ethyl acetate phase was separated and washed with water and brine, then dried over magnesium sulfate. Evaporation of the ethyl acetate afforded the title compound, IR 1780 cm -1 ( ⁇ -lactam carbonyl).
• the ethyl acetate solution was washed successively with 75 ml aliquots of 0.5N hydrochloric acid, water, saturated sodium bicarbonate solution, water and brine then dried over magnesium sulfate.
• Theethyl acetate was evaporated at reduced pressure and the resulting product was purified by chromatography on silica gel using ethyl acetate: hexane (1:1),IR 1785 cm- 1 ( S -lactam carbonyl).

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Communicable Diseases (AREA)
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• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
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• Cephalosporin Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1984
  • 1984-04-02 US US06/595,844 patent/US4914091A/en not_active Expired - Lifetime
  • 1984-09-27 JP JP59200689A patent/JPS60209589A/ja active Pending
  • 1984-12-20 EP EP84116013A patent/EP0157000A3/de not_active Withdrawn
  • 1984-12-21 AU AU37021/84A patent/AU571042B2/en not_active Ceased
  • 1984-12-21 DK DK626984A patent/DK626984A/da not_active Application Discontinuation
  • 1984-12-23 IL IL73918A patent/IL73918A0/xx unknown
• 1985
  • 1985-01-04 NZ NZ210761A patent/NZ210761A/xx unknown
  • 1985-01-04 ES ES539367A patent/ES8606873A1/es not_active Expired
  • 1985-01-10 HU HU8578A patent/HU194252B/hu unknown
  • 1985-01-10 ZA ZA85240A patent/ZA85240B/xx unknown
  • 1985-01-17 KR KR1019850000263A patent/KR870001007B1/ko not_active Expired
  • 1985-03-27 PH PH32057A patent/PH20664A/en unknown
  • 1985-03-28 PT PT80180A patent/PT80180B/pt not_active IP Right Cessation
  • 1985-04-01 FI FI851306A patent/FI851306A7/fi not_active Application Discontinuation
  • 1985-04-01 NO NO851336A patent/NO851336L/no unknown
  • 1985-11-26 ES ES549294A patent/ES8606359A1/es not_active Expired

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